This project aims to identify genetic variants that contribute to the comorbidity of substance use disorders (SUD) and mood disorders (MD). Each of these disorders represents among the greatest disease burdens worldwide. Yet their frequent co-morbidity is itself a major public health problem: individuals in whom SUD and MD co-occur have clinical outcomes that are dramatically worse than those of individuals who suffer from only one of these conditions. Our limited understanding of the factors that generate SUD/MD co-morbidity hinders our ability to prevent it or to successfully treat affected individuals. In particular, although both types of disorder are highly heritable, it remains unclear whether the set of genetic variants influencing risk for SUD overlaps with the genetic variants contributing to risk for MD, or even whether there are variants that specifically predispose to SUD/MD co-morbidity. To elucidate the genetic basis of SUD/MD comorbidity this project will analyze comprehensive genetic variation data obtained through whole genome sequencing (WGS) of members of 26 pedigrees from the genetically related population isolates of Antioquia, Colombia (CO) and the Central Valley of Costa Rica (CR). The project will leverage the infrastructure and data (extensive phenotypes, high-resolution genome-wide genotypes, and deep WGS) from an existing study of 800 individuals in these pedigrees that has focused on identifying genetic variants contributing to severe bipolar disorder (BP-I) and has already genetically mapped loci for both BP-I and for BP-I endophenotypes. The majority of BP-I individuals worldwide demonstrate comorbidity with one or more SUD, and preliminary data indicate that these pedigrees include a substantial number of members comorbid for SUD with either BP-I or another form of MD. To conduct genetic investigations of SUD/MD comorbidity this project will: 1) Recruit 300 additional 1st degree relatives of existing subjects, targeting individuals affected with SUD and a broad spectrum of MD, achieving a total sample of 1100 individuals; 2) Conduct phenotypic assessments in the 1100-person sample to quantify substance use, diagnose SUD, and identify heritable endophenotypes for SUD and SUD/MD comorbidity; 3) Perform additional genotyping and WGS to achieve comprehensive genetic variation data for the entire 1100-person sample; 4) Carry out genetic mapping studies to identify variants contributing to SUD, SUD/MD comorbidity, and to SUD-related endophenotypes. Future studies will follow-up our results in a variety of independent study samples from CO, CR and the U.S.